Journal
GENOME RESEARCH
Volume 22, Issue 11, Pages 2120-2129Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.137596.112
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Funding
- Stand Up to Cancer Dream Team Translational Research Grant, a Program of the Entertainment Industry Foundation [SU2C-AACR-DT0209]
- Uterine Cancer SPORE grant (NIH/NCI) [P50 CA098258, U01 CA168394]
- Conquer Cancer Foundation of the American Society of Clinical Oncology
- NIH/NCI [R21CA152432]
- Keck Center Computational Cancer Biology Training Program of the Gulf Coast Consortia (CPRIT) [RP101489]
- G.S. Hogan Gastrointestinal Research Fund
- Lorraine Dell Program in Bioinformatics for Personalization of Cancer Medicine
- TCGA GDAC Grant (NIH/NCI) [U24 CA143883]
- Institutional Core grant (NIH/NCI) [CA016672]
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Endometrial cancer is the most common gynecological malignancy, with more than 280,000 cases occurring annually worldwide. Although previous studies have identified important common somatic mutations in endometrial cancer, they have primarily focused on a small set of known cancer genes and have thus provided a limited view of the molecular basis underlying this disease. Here we have developed an integrated systems-biology approach to identifying novel cancer genes contributing to endometrial tumorigenesis. We first performed whole-exome sequencing on 13 endometrial cancers and matched normal samples, systematically identifying somatic alterations with high precision and sensitivity. We then combined bioinformatics prioritization with high-throughput screening (including both shRNA-mediated knockdown and expression of wild-type and mutant constructs) in a highly sensitive cell viability assay. Our results revealed 12 potential driver cancer genes including 10 tumor-suppressor candidates (ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11) and two oncogene candidates (ERBB3 and RPS6KC1). The results in the sensor cell line were recapitulated by siRNA-mediated knockdown in endometrial cancer cell lines. Focusing on ARID1A, we integrated mutation profiles with functional proteomics in 222 endometrial cancer samples, demonstrating that ARID1A mutations frequently co-occur with mutations in the phosphatidylinositol 3-kinase (PI3K) pathway and are associated with PI3K pathway activation. siRNA knockdown in endometrial cancer cell lines increased AKT phosphorylation supporting ARID1A as a novel regulator of PI3K pathway activity. Our study presents the first unbiased view of somatic coding mutations in endometrial cancer and provides functional evidence for diverse driver genes and mutations in this disease.
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